The pharmacogenetics of drug hypersensitivity

Abstract

Drug hypersensitivity reactions and severe cutaneous adverse drug reactions such as Stevens-Johnson Syndrome and toxic epidermal necrolysis (SJS/TEN) are examples of serious adverse drug reactions mediated through a combination of metabolic and immunological mechanisms that are not predictable based on the pharmacological properties of the drug. The major histocompatibility complex (MHC) plays a major role in the pathophysiology of these diseases and the discovery of new associations between these syndromes and specific human leukocyte antigens (HLA) has created the promise that these traditionally unpredictable drug reactions could be predicted and hence prevented. Examples have included SJS/TEN associated with carbamazepine (HLA-B*1502) and allopurinol (HLA-B*5801) and HLA-B*5701 with both abacavir hypersensitivity syndrome and flucloxacillin drug-induced liver disease. Despite this, several hurdles exist to defining the generalisability of these associations across ethnicity as well as the translation of these associations into pharmacogenetic tests that are routinely used in the clinical setting. HLAB* 5701 screening to prevent abacavir hypersensitivity syndrome is an example of a test now in widespread routine clinical use in the developed world.